Preliminary studies have shown that production of lactose, the major osmotic component of milk, in lactating guinea pig mammary gland slices is inhibited by the phosphodiesterase inhibitors theophylline and papaverine and by normal and dibutyryl 3',5'-cyclic adenosine monophosphate (cAMP). Partial inhibition was also obtained with epinephrine, isoproterenol and glucagon which increase cAMP levels in some tissues. These observations suggest that cAMP may have an inhibitory role in the regulation of lactation. The proposed project will examine this possibility as follows: (1) Study the specificity of the effect in vitro by testing the abiltiy of other cyclic nucleotides and related phosphate compounds to inhibit lactose production and determine which hormones (individually or in combination) yield maximum inhibition. (2) Measure cAMP levels in slices during hormone-induced inhibition of lactose production. (3) Measure adenylate cyclase and phosphodiesterase activities during in vitro inhibition and establish the sequence and timing of these events. (4) Study the influence of cAMP on mammary gland lactose synthetase. (5) Characterize the fine structural parameters of the inhibition effect. (6) Measure cAMP, adenylate cyclase and phosphodiesterase in virgin, pregnant, lactating and involuted guinea pig mammary glands to establish whether the in vitro effects observed in (1-5) may be applied in vivo. (7) Follow the same 3 parameters using animals ovariectomized in late pregnancy to observe the effects of ovarian hormone withdrawl and then attempt to reverse the changes using hormone therapy. (8) Determine whether the same inhibitory effect occurs in the rat mammary tumor R3230AC, which secretes a milk-like fluid after estrogen treatment of the host. It is anticipated that these studies will shed light on the regulatory factors which, at or near parturition, redirect the activities of mammary gland epithelium from growth and differentiation to that of milk secretion.